title: Infusion of haplo-identical killer immunoglobulin-like receptor ligand mismatched NK cells for relapsed myeloma in the setting of autologous stem cell transplantation.
abstract: Killer immunoglobulin-like receptor (KIR)-ligand mismatched natural killer (NK) cells play a key role in achieving durable remission after haplo-identical transplantation for acute myeloid leukaemia. We investigated the feasibility of transfusing haplo-identical, T-cell depleted, KIR-ligand mismatched NK cells, after conditioning therapy with melphalan and fludarabine, to patients with advanced multiple myeloma (MM) followed by delayed rescue with autologous stem cells. No graft-versus-host disease or failure of autologous stem cells to engraft was observed. There was significant variation in the number of allo-reactive NK cells transfused. However, all NK products containing allo-reactive NK cells killed the NK cell target K562, the MM cell line U266, and recipient MM cells when available. Post NK cell infusion there was a rise in endogenous interleukin-15 accompanied by increasing donor chimaerism. Donor chimaerism was eventually lost, which correlated with the emergence of potent host anti-donor responses indicating that the immunosuppressive properties of the conditioning regimen require further optimization. Further, blocking of inhibitory KIR-ligands with anti-human leucocyte antigen antibody substantially enhanced killing of MM cells thus highlighting the potential for modulating NK/MM cell interaction. Encouragingly, 50% of patients achieved (near) complete remission. These data set the stage for future studies of KIR-ligand mismatched NK cell therapy in the autologous setting.
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Jumei
authors.initials: J
authors.lastname: Shi
authors.forename: Guido
authors.initials: G
authors.lastname: Tricot
authors.forename: Susann
authors.initials: S
authors.lastname: Szmania
authors.forename: Nancy
authors.initials: N
authors.lastname: Rosen
authors.forename: Tarun K
authors.initials: TK
authors.lastname: Garg
authors.forename: Priyangi A
authors.initials: PA
authors.lastname: Malaviarachchi
authors.forename: Amberly
authors.initials: A
authors.lastname: Moreno
authors.forename: Bo
authors.initials: B
authors.lastname: Dupont
authors.forename: Katharine C
authors.initials: KC
authors.lastname: Hsu
authors.forename: Lee Ann
authors.initials: LA
authors.lastname: Baxter-Lowe
authors.forename: Michele
authors.initials: M
authors.lastname: Cottler-Fox
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
mesh_terms: D000328:Adult; D000368:Aged; D002460:Cell Line; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology / Q000637:transplantation*; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy*; D054340:Receptors, KIR / Q000276:immunology*; D012008:Recurrence; D014182:Transplantation, Autologous; D016896:Treatment Outcome
chemical_list: D008024:Ligands; D054340:Receptors, KIR